αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

Abstract

Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme inde novocarnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis.

Interplay between altered metabolism and DNA damage and repair in ovarian cancer

“…[24] Furthermore, we recently found that inhibition of wildtype IDH1 and depletion of αKG specifically inhibits HR-mediated DSB repair via a carnitine-mediated histone acetylation. [116] In CCNE1-driven models, this axis was necessary for resistance to DNA damaging agents such as cisplatin and olaparib.…”

“…As we have discussed above, prior studies have interrogated a link between ACLY and both mutant and wildtype IDH1 and DNA repair. [24,110,116,156] However, many other TCA cycle enzymes and metabolites that affect the epigenome are also altered in ovarian cancer. As DNA repair genes such as BRCA1 are hypermethylated in ovarian cancer, this raises the intriguing question as to whether this can be modulating via metabolism.…”